Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

Xiaolin Luo; Rui Liao; Kaisa L Hanley; Helen He Zhu; Kirsten N Malo; Carolyn Hernandez; Xufu Wei; Nissi M Varki; Nazilla Alderson; Catherine Chu; Shuangwei Li; Jia Fan; Rohit Loomba; Shuang-Jian Qiu; Gen-Sheng Feng

doi:10.1016/j.celrep.2016.11.048

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

Cell Rep. 2016 Dec 13;17(11):2979-2993. doi: 10.1016/j.celrep.2016.11.048.

Authors

Affiliations

¹ Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing 40016, China.
³ Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Department of Medicine, NAFLD Research Center, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Hepatobiliary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing 40016, China.
⁶ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁷ Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: gfeng@ucsd.edu.

Abstract

The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

Keywords: PTEN; Shp2; liver tumorigenesis; non-alcoholic steatohepatitis; tumor suppressor; tumor-initiating cells.

MeSH terms

Animals
Carcinogenesis / genetics*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Humans
JNK Mitogen-Activated Protein Kinases / genetics
Liver / metabolism
Liver / pathology
Liver Neoplasms / genetics
Liver Neoplasms / pathology
Mice, Knockout
Neoplastic Stem Cells / metabolism
Non-alcoholic Fatty Liver Disease / genetics*
Non-alcoholic Fatty Liver Disease / pathology
PTEN Phosphohydrolase / genetics*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
Proto-Oncogene Mas
Signal Transduction

Substances

MAS1 protein, human
Proto-Oncogene Mas
JNK Mitogen-Activated Protein Kinases
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Ptpn11 protein, mouse
PTEN Phosphohydrolase
PTEN protein, human

Abstract

MeSH terms

Substances

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